WO2018193346A1 - Effervescent compositions comprising chlorpromazine or salt thereof - Google Patents

Effervescent compositions comprising chlorpromazine or salt thereof Download PDF

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Publication number
WO2018193346A1
WO2018193346A1 PCT/IB2018/052584 IB2018052584W WO2018193346A1 WO 2018193346 A1 WO2018193346 A1 WO 2018193346A1 IB 2018052584 W IB2018052584 W IB 2018052584W WO 2018193346 A1 WO2018193346 A1 WO 2018193346A1
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WIPO (PCT)
Prior art keywords
chlorpromazine
effervescent
agent
acid
salt
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Application number
PCT/IB2018/052584
Other languages
French (fr)
Inventor
Sivakumar Venkata BOBBA
Bhimrao Jadhav
Dhananjay Shinde
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Zenvision Pharma Llp
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Publication date
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Publication of WO2018193346A1 publication Critical patent/WO2018193346A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to effervescent compositions comprising chlorpromazine or salt thereof for the treatment of psychotic disorders.
  • Antipsychotic drugs are a class of medicines used to treat psychosis and other mental and emotional conditions.
  • Psychosis is a serious mental disorder (as schizophrenia) characterized by defective or lost contact with reality often with hallucinations or delusions.
  • Psychosis is an end-stage condition arising from a variety of possible causes.
  • Anti-psychotic drugs control the symptoms of psychosis, and in many cases are effective in controlling the symptoms of other disorders that may lead to psychosis.
  • Antipsychotics are commonly categorized into two drug classes, first-generation antipsychotics and second-generation antipsychotics.
  • the first-generation antipsychotics are like Chlorpromazine, Flupenthixol, Haloperidol, Trifluoperazine and Zuclopenthixol.
  • the second generation antipsychotics are like Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone and Quetiapine
  • Chlorpromazine hydrochloride is phenothiazine class of antipsychotic drug.
  • Chemically chlorpromazine hydrochloride is a dimethylamine derivative of phenothiazine, has a chemical formula of 2-chloro-10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride and its molecular weight is 355.33. Its empirical formula is C17H20CI2N2S.
  • Chlorpromazine hydrochloride is represented by compound of structural formula I
  • Chlorpromazine hydrochloride occurs as white or slightly creamy white, odorless, crystalline powder which darkens on prolonged exposure to light. Chlorpromazine hydrochloride is soluble in water, alcohol and chloroform but practically insoluble in ether, benzene.
  • Chlorpromazine hydrochloride tablet and injection of Glaxosmithkline were approved in USA prior to 1982 under the trade name Thora3 ⁇ 4aBd are discontinued from the market; although the currently available dosage forms in USA are tablet (10mg, 25mg, 50mg, 100mg, 200mg) of USL Pharma and injection (25mg/ml) of Eurohealth.
  • the products are indicated for the treatment of psychotic disorders, schizophrenia, nausea and vomiting, for relief of restlessness and apprehension before surgery, acute intermittent porphyria, adjunct in the treatment of tetanus, manic type of manic-depressive illness and relief of intractable hiccups
  • U.S. Patent Publication No. 20050074489 discloses effervescent compositions.
  • This patent publication generically discloses effervescent compositions among a laundry list of active therapeutic ingredient.
  • this patent publication does not disclose or teaches specifically effervescent compositions of Chlorpromazine.
  • U.S. Patent Publication No. 20150201665 discloses generically liquid or solution based carbonated beverage of active therapeutic ingredient. This patent publication generically discloses laundry list of active therapeutic ingredient and does not teach specifically regarding Chlorpromazine. International Journal of Pharmaceutical & Biological Archives 2011 ; 2(4): 1 175-1178 discloses "Formulation and Evaluation of Mouth Dissolving Tablets of Chlorpromazine HCI". Currently, the commercially marketed product of Chlorpromazine hydrochloride is available in the form of conventional immediate release tablet and injection.
  • Chlorpromazine or salt thereof suffer from several drawbacks in terms of bioavailability and in terms of release of active ingredient from the dosage form. Also they have several adverse effects such as Drowsiness, Jaundice, Hematological Disorders, Agranulocytosis, Hypotensive Effects, electrocardiogram Changes, Extrapyramidal Symptoms, Class effect, Motor Restlessness, Pseudo Parkinsonism, Tardive Dyskinesia, Behavioral Effects, Other CNS Effects such as Neuroleptic Malignant Syndrome, Cerebral edema, Convulsive seizures, Allergic Reactions such as mild urticarial type of photosensitivity, exfoliative dermatitis, Contact dermatitis, Endocrine Disorders, Autonomic Reactions, Skin Pigmentation, Ocular Changes.
  • Chlorpromazine is classified as BCS Class 3 drug, which is high soluble and low permeable.
  • the gastrointestinal membrane permeability of chlorpromazine is low; therefore, absorption is limited by the permeation rate. Due to its low permeability and high first metabolism the oral systemic bioavailability of Chlorpromazine is only 30%.
  • compositions comprising chlorpromazine or salt thereof which allows more permeation of chlorpromazine through gastrointestinal membrane, minimum loss of drug during the first pass metabolism and efficient release of chlorpromazine.
  • a first aspect of the present invention is to provide effervescent compositions comprising chlorpromazine or salt thereof.
  • another aspect of the present invention is to provide effervescent compositions comprising chlorpromazine or salt thereof along with one or more pharmaceutically acceptable excipient.
  • In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of chlorpromazine or salt thereof.
  • In another aspect of the present invention is to provide method of treating psychotic disorders by administering effervescent composition comprising chlorpromazine or salt thereof.
  • the present invention relates to effervescent compositions comprising chlorpromazine or salt thereof.
  • the effervescent compositions of the present inventions may comprise Chlorpromazine base or its salts like Chlorpromazine hydrochloride, Chlorpromazine embonate and Chlorpromazine succinate.
  • the effervescent compositions of the present inventions preferably may contain chlorpromazine hydrochloride.
  • the effervescent compositions of the present invention may be in the form of composition which is meant to be administered directly into the gastrointestinal tract via oral route.
  • the effervescent compositions of the present invention may float into the gastrointestinal tract.
  • compositions of the present invention may be in the form of composition which is meant to be added into the glass of water just before administration and the drug solution or dispersion is to be consumed immediately.
  • effervescent composition according to present invention means the composition of chlorpromazine or salt thereof which upon contact with aqueous media produces carbon dioxide.
  • effervescent composition according to present invention also means the composition of chlorpromazine or salt thereof which comprises at least one acidic agent.
  • effervescent composition according to present invention also means the composition of chlorpromazine or salt thereof which comprises at least one basic agent.
  • effervescent compositions of the present invention offer enhanced dissolution and absorption of chlorpromazine or salt thereof resulting in increased bioavailability. According to present invention chlorpromazine or salt thereof are absorbed better from effervescent formulations as compared to dry, solid oral formulations.
  • the effervescent compositions of the present invention provide quick dissolution upon contact with aqueous media, liberation of CO 2 result in pleasant taste, improved permeation across GIT membrane therefore enhanced absorption.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention may be in the form of effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet.
  • the effervescent compositions comprising chlorpromazine or salt thereof may contain one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
  • diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof.
  • acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof.
  • basic agents include but not limited to sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate, glycine carbonate or mixture thereof.
  • binders include but not limited to, ethyl cellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof.
  • disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof.
  • solubilizing agent or surfactant examples include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
  • sweeteners include but not limited to acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof.
  • flavor examples include but not limited to fruit flavor, peppermint flavor, Sour cherry flavor, orange flavor or mixture thereof.
  • pH regulating agent examples include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.
  • stabilizing agent examples include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
  • antioxidants include but not limited to BHA, BHT, Sodium sulfate or mixture thereof.
  • lubricant examples include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof.
  • glidant examples include but not limited to silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or mixture thereof.
  • coloring agents include but not limited to titanium dioxide and dye suitable for food such as those known as FD & C dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika or mixture thereof.
  • In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising chlorpromazine or salt thereof.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention can be manufactured by process such as direct compression, dry granulation (slugging), wet granulation, heat fusion, roller compaction and hot melt extrusion.
  • the process of manufacturing effervescent composition comprising mixing chlorpromazine or salt thereof along with one or more one or more pharmaceutically acceptable excipient like acidic agent, basic agent, diluents, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
  • the manufacturing process may involve direct compression, dry granulation or wet granulation approach.
  • the effervescent composition can comprise any suitable amount of the chlorpromazine or salt thereof in order to produce an effective blood level of the chlorpromazine in the psychotic disorder.
  • the weight percentage of chlorpromazine or salt thereof can be 0.5% to 80%, preferably 2 to 50% based on the total weight of composition.
  • the amount of chlorpromazine or salt thereof may ranges from 2mg to 400mg, preferably 5mg to 300mg, more preferably 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg and 250mg.
  • the effervescent composition can comprise any suitable amount of the one or more pharmaceutically acceptable excipient like acidic agent, basic agent, diluents, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
  • the acid agent is present in the effervescent composition in an amount of about 1% to about 60% based on the total weight of the composition; preferably in an amount of about 3% to about 45%; more preferably in an amount of about 5% to about 30%.
  • the basic agent is present in the effervescent composition in an amount of about 5% to about 80% based on the total weight of the composition; preferably in an amount of about 20% to about 50%.
  • the binder is present in the effervescent composition in an amount of about 0.5% to about 30% based on the total weight of the composition; preferably in an amount of about 1% to about 10%.
  • the disintegrant is present in the effervescent composition in an amount of about 1 % to about 20% based on the weight of the composition.
  • the solubilizing agent is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition.
  • the sweetener is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.1% to about 2%.
  • the flavor is present in the effervescent composition in an amount of about 0% to about 10% based on the total weight of the composition; preferably in an amount of about 0.5% to about 3%; more preferably in an amount of about 0.2% to about 2%.
  • the lubricant is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.2 to about 4%.
  • the glidant is present in the effervescent composition in an amount of about 0.1 % to about 20% based on the total weight of the composition.
  • the coloring agent is present in the effervescent composition in an amount of about 0.1 % to about 3.5% based on the total weight of the composition.
  • the antioxidant is present in the effervescent composition in an amount of about 0.01 % to about 0.1 % based on the total weight of the composition.
  • an acid to base ratio in the formulation ranging from 1 :3 to 3:1.
  • the acidic agents may be like citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof.
  • acidic agent may be citric acid, tartaric acid or mixture thereof.
  • the basic agents may be like sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate or mixture thereof.
  • basic agent may be sodium bicarbonate, sodium carbonate or mixture thereof
  • Acidic agent and basic agent present in the effervescent composition reacts with aqueous media; wherein acid neutralizes base with the liberation of carbon dioxide and formation of acid salt and water.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction.
  • the carbon dioxide produced by effervescent reaction allows enhanced permeability of chlorpromazine or salt thereof due to an alteration of the paracellular and transcellular pathway.
  • the carbon dioxide produced by effervescent reaction alters (widens) the intercellular space between cells, which leads to greater absorption of active ingredients and also it promotes transcellular absorption by Inducing a change in the cell membrane structure.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction.
  • the said dosage form allows minimum loss of chlorpromazine through first pass metabolism results in increased systemic bioavailability of chlorpromazine in the treatment of psychotic disorders.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention show quick disintegration and dissolution upon contact with water.
  • the effervescent composition of the present invention when formulated as tablet has a disintegration time of about 300 seconds or less.
  • the disintegration time of the effervescent tablet is about 180 seconds or less and more preferably about 90 seconds or less.
  • the disintegration time is measured in 200 ml of water at room temperature of about 25°C ⁇ 5°C.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention upon dissolution has pH ranges from 3 to 6.5.
  • the pH is measured in 200 ml of water at room temperature of about 25°C ⁇ 5°C.
  • the effervescent compositions comprising chlorpromazine or salt thereof of the present invention has pleasant taste which allows patient acceptability and better compliance in the treatment psychotic disorder.
  • compositions comprising chlorpromazine or salt thereof of the present invention can be made up of any weight with suitable quantities of chlorpromazine or salt thereof and pharmaceutically acceptable excipient.
  • effervescent compositions of present invention like appearance, thickness, weight variation, hardness, friability, smell, taste, after taste were found to be satisfactory.
  • effervescent composition comprising chlorpromazine or salt thereof.
  • the concentrations of active ingredient and excipient in the effervescent compositions has been optimized which allows better patient compliance in the treatment of psychotic disorders, schizophrenia, nausea and vomiting, for relief of restlessness and apprehension before surgery, acute intermittent porphyria, adjunct in the treatment of tetanus, manic type of manic-depressive illness, relief of intractable hiccups with less adverse effect such as Drowsiness, Jaundice, Hematological Disorders, Agranulocytosis, Hypotensive Effects, electrocardiogram Changes, Extrapyramidal Symptoms, Class effect, Motor Restless ness, Pseudo parkinsonism, Tardive Dyskinesia, Behavioral Effects, Other CNS Effects such as Neuroleptic Malignant Syndrome, Cerebral edema, Convulsive seizures, Allergic Reactions such as mild urticarial type of photosensitivity, exfoliative dermatitis, Contact dermatitis, Endocrine Disorders, Autonomic Reactions,
  • compositions comprising chlorpromazine or salt thereof of the present invention can be packaged in suitable air tight containers, moisture proof packs and optionally oxygen busters.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Polyvinylprrolidone, and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 3 The blend of step 1 was lubricated with part quantity Magnesium stearate of step 2.
  • step 3 The blend of step 3 was fed into Roller compactor to obtain flex/ribbons.
  • Milled granules of step-5 were mixed with previously weighed and sifted Sucralose and Peppermint flavor (ASTM#40) and lubricated by mixing with remaining quantity of Magnesium stearate of step -2.
  • step 6 The blend of step 6 was compressed using suitable tooling fitted to compression machine.
  • Example 2 The blend of step 6 was compressed using suitable tooling fitted to compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate and Mannitol were sifted through ASTM #40 and mixed in a granulator.
  • Step-3 Raw materials from Step-1 were granulated using binder of step -2; obtained granules were dried and milled.
  • Magnesium stearate was sifted through ASTM #60.
  • step 4 was lubricated with Magnesium stearate of step 5.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid, Tartaric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium carbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid was sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium carbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid, Tartaric acid and Sodium citrate were sifted through #20 and mixed. 2. Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Tartaric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with Magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.

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Abstract

The present disclosure relates to effervescent compositions comprising Chlorpromazine or salt thereof and manufacturing process for the same. The effervescent composition comprises at least one acidic agent and at least one basic agent along with one or more pharmaceutically acceptable excipient. The effervescent compositions provide quick dissolution upon contact with aqueous media, liberation of carbon dioxide results in pleasant taste, improved permeation across gastrointestinal membrane therefore enhanced absorption in the treatment of psychotic disorders.

Description

EFFERVESCENT COMPOSITIONS COMPRISING CHLORPROMAZINE OR
SALT THEREOF
FIELD OF THE INVENTION
The present invention relates to effervescent compositions comprising chlorpromazine or salt thereof for the treatment of psychotic disorders.
BACKGROUND OF THE INVENTION
Antipsychotic drugs are a class of medicines used to treat psychosis and other mental and emotional conditions. Psychosis is a serious mental disorder (as schizophrenia) characterized by defective or lost contact with reality often with hallucinations or delusions. Psychosis is an end-stage condition arising from a variety of possible causes. Anti-psychotic drugs control the symptoms of psychosis, and in many cases are effective in controlling the symptoms of other disorders that may lead to psychosis.
Antipsychotics are commonly categorized into two drug classes, first-generation antipsychotics and second-generation antipsychotics. The first-generation antipsychotics are like Chlorpromazine, Flupenthixol, Haloperidol, Trifluoperazine and Zuclopenthixol. The second generation antipsychotics are like Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone and Quetiapine
Chlorpromazine hydrochloride is phenothiazine class of antipsychotic drug. Chemically chlorpromazine hydrochloride is a dimethylamine derivative of phenothiazine, has a chemical formula of 2-chloro-10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride and its molecular weight is 355.33. Its empirical formula is C17H20CI2N2S. Chlorpromazine hydrochloride is represented by compound of structural formula I
Figure imgf000003_0001
Chlorpromazine hydrochloride occurs as white or slightly creamy white, odorless, crystalline powder which darkens on prolonged exposure to light. Chlorpromazine hydrochloride is soluble in water, alcohol and chloroform but practically insoluble in ether, benzene.
Chlorpromazine hydrochloride tablet and injection of Glaxosmithkline were approved in USA prior to 1982 under the trade name Thora¾aBd are discontinued from the market; although the currently available dosage forms in USA are tablet (10mg, 25mg, 50mg, 100mg, 200mg) of USL Pharma and injection (25mg/ml) of Eurohealth. The products are indicated for the treatment of psychotic disorders, schizophrenia, nausea and vomiting, for relief of restlessness and apprehension before surgery, acute intermittent porphyria, adjunct in the treatment of tetanus, manic type of manic-depressive illness and relief of intractable hiccups
U.S. Patent Publication No. 20050074489 discloses effervescent compositions. This patent publication generically discloses effervescent compositions among a laundry list of active therapeutic ingredient. However, this patent publication does not disclose or teaches specifically effervescent compositions of Chlorpromazine.
U.S. Patent Publication No. 20150201665 discloses generically liquid or solution based carbonated beverage of active therapeutic ingredient. This patent publication generically discloses laundry list of active therapeutic ingredient and does not teach specifically regarding Chlorpromazine. International Journal of Pharmaceutical & Biological Archives 2011 ; 2(4): 1 175-1178 discloses "Formulation and Evaluation of Mouth Dissolving Tablets of Chlorpromazine HCI". Currently, the commercially marketed product of Chlorpromazine hydrochloride is available in the form of conventional immediate release tablet and injection.
The commercially marketed product of Chlorpromazine or salt thereof as well as the product known in the prior art suffer from several drawbacks in terms of bioavailability and in terms of release of active ingredient from the dosage form. Also they have several adverse effects such as Drowsiness, Jaundice, Hematological Disorders, Agranulocytosis, Hypotensive Effects, electrocardiogram Changes, Extrapyramidal Symptoms, Class effect, Motor Restlessness, Pseudo Parkinsonism, Tardive Dyskinesia, Behavioral Effects, Other CNS Effects such as Neuroleptic Malignant Syndrome, Cerebral edema, Convulsive seizures, Allergic Reactions such as mild urticarial type of photosensitivity, exfoliative dermatitis, Contact dermatitis, Endocrine Disorders, Autonomic Reactions, Skin Pigmentation, Ocular Changes.
According to the Biopharmaceutical Classification System (BCS), Chlorpromazine is classified as BCS Class 3 drug, which is high soluble and low permeable. The gastrointestinal membrane permeability of chlorpromazine is low; therefore, absorption is limited by the permeation rate. Due to its low permeability and high first metabolism the oral systemic bioavailability of Chlorpromazine is only 30%. Thus, there is an unmet need in the art to provide a composition which provides more permeation of chlorpromazine through gastrointestinal membrane with minimum loss of drug during the first pass metabolism and efficient release of chlorpromazine.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide effervescent compositions comprising chlorpromazine or salt thereof which allows more permeation of chlorpromazine through gastrointestinal membrane, minimum loss of drug during the first pass metabolism and efficient release of chlorpromazine.
It is another object of the present invention to provide effervescent compositions comprising chlorpromazine or salt thereof with more bioavailability in the treatment of psychotic disorders.
It is another object of the present invention to provide effervescent compositions which results in better patient compliance in the treatment of psychotic disorders with less adverse effects.
It is yet another object of the present invention to provide a method for treating psychotic disorders involving administration of the effervescent compositions comprising chlorpromazine or salt thereof.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide effervescent compositions comprising chlorpromazine or salt thereof. In another aspect of the present invention is to provide effervescent compositions comprising chlorpromazine or salt thereof along with one or more pharmaceutically acceptable excipient.
In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of chlorpromazine or salt thereof.
In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of chlorpromazine or salt thereof comprising one or more pharmaceutically acceptable excipient. In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising chlorpromazine or salt thereof.
In another aspect of the present invention is to provide method of treating psychotic disorders by administering effervescent composition comprising chlorpromazine or salt thereof.
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to effervescent compositions comprising chlorpromazine or salt thereof.
The effervescent compositions of the present inventions may comprise Chlorpromazine base or its salts like Chlorpromazine hydrochloride, Chlorpromazine embonate and Chlorpromazine succinate. The effervescent compositions of the present inventions preferably may contain chlorpromazine hydrochloride.
The effervescent compositions of the present invention may be in the form of composition which is meant to be administered directly into the gastrointestinal tract via oral route. The effervescent compositions of the present invention may float into the gastrointestinal tract.
The effervescent compositions of the present invention may be in the form of composition which is meant to be added into the glass of water just before administration and the drug solution or dispersion is to be consumed immediately.
The term effervescent composition according to present invention means the composition of chlorpromazine or salt thereof which upon contact with aqueous media produces carbon dioxide. The term effervescent composition according to present invention also means the composition of chlorpromazine or salt thereof which comprises at least one acidic agent. The term effervescent composition according to present invention also means the composition of chlorpromazine or salt thereof which comprises at least one basic agent.
Conventional solid delivery systemsoiflorpromazine or salt thereof such as tablet must be ingested with water to disintegrate the dosage form, inside the stomach it has to disintegrate into small particles and the active ingredient has to be solubilized such that it can be absorbed into the blood plasma of the patient. The disintegration and solubilization processes for solid dosage forms delay the bioavailability of the active ingredient. The effervescent compositions of the present invention offer enhanced dissolution and absorption of chlorpromazine or salt thereof resulting in increased bioavailability. According to present invention chlorpromazine or salt thereof are absorbed better from effervescent formulations as compared to dry, solid oral formulations. The effervescent compositions of the present invention provide quick dissolution upon contact with aqueous media, liberation of CO2 result in pleasant taste, improved permeation across GIT membrane therefore enhanced absorption.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention may be in the form of effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet.
The effervescent compositions comprising chlorpromazine or salt thereof may contain one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
The examples of diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof. The examples of acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof. The examples of basic agents include but not limited to sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate, glycine carbonate or mixture thereof.
The examples of binders include but not limited to, ethyl cellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof.
The examples of disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof.
The examples of solubilizing agent or surfactant include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
The examples of sweeteners include but not limited to acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof.
The examples of flavor include but not limited to fruit flavor, peppermint flavor, Sour cherry flavor, orange flavor or mixture thereof.
The examples of pH regulating agent include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof. The examples of stabilizing agent include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
The examples of antioxidants include but not limited to BHA, BHT, Sodium sulfate or mixture thereof.
The examples of lubricant include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof.
The examples of glidant include but not limited to silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or mixture thereof.
The examples of coloring agents include but not limited to titanium dioxide and dye suitable for food such as those known as FD & C dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika or mixture thereof.
In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising chlorpromazine or salt thereof.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention can be manufactured by process such as direct compression, dry granulation (slugging), wet granulation, heat fusion, roller compaction and hot melt extrusion. The process of manufacturing effervescent composition comprising mixing chlorpromazine or salt thereof along with one or more one or more pharmaceutically acceptable excipient like acidic agent, basic agent, diluents, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents. Preferably the manufacturing process may involve direct compression, dry granulation or wet granulation approach. The effervescent composition can comprise any suitable amount of the chlorpromazine or salt thereof in order to produce an effective blood level of the chlorpromazine in the psychotic disorder. The weight percentage of chlorpromazine or salt thereof can be 0.5% to 80%, preferably 2 to 50% based on the total weight of composition. The amount of chlorpromazine or salt thereof may ranges from 2mg to 400mg, preferably 5mg to 300mg, more preferably 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg and 250mg.
The effervescent composition can comprise any suitable amount of the one or more pharmaceutically acceptable excipient like acidic agent, basic agent, diluents, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
The acid agent is present in the effervescent composition in an amount of about 1% to about 60% based on the total weight of the composition; preferably in an amount of about 3% to about 45%; more preferably in an amount of about 5% to about 30%. The basic agent is present in the effervescent composition in an amount of about 5% to about 80% based on the total weight of the composition; preferably in an amount of about 20% to about 50%.
The binder is present in the effervescent composition in an amount of about 0.5% to about 30% based on the total weight of the composition; preferably in an amount of about 1% to about 10%. The disintegrant is present in the effervescent composition in an amount of about 1 % to about 20% based on the weight of the composition.
The solubilizing agent is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition. The sweetener is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.1% to about 2%.
The flavor is present in the effervescent composition in an amount of about 0% to about 10% based on the total weight of the composition; preferably in an amount of about 0.5% to about 3%; more preferably in an amount of about 0.2% to about 2%. The lubricant is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.2 to about 4%. The glidant is present in the effervescent composition in an amount of about 0.1 % to about 20% based on the total weight of the composition. The coloring agent is present in the effervescent composition in an amount of about 0.1 % to about 3.5% based on the total weight of the composition. The antioxidant is present in the effervescent composition in an amount of about 0.01 % to about 0.1 % based on the total weight of the composition.
According to present invention, defined amount of acid and base sources are used to obtain a good water soluble novel effervescent composition, which comprises chlorpromazine or salt thereof. Accordingly, it was observed that an acid to base ratio in the formulation ranging from 1 :3 to 3:1. The acidic agents may be like citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof. Preferably acidic agent may be citric acid, tartaric acid or mixture thereof. The basic agents may be like sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate or mixture thereof. Preferably basic agent may be sodium bicarbonate, sodium carbonate or mixture thereof
Acidic agent and basic agent present in the effervescent composition reacts with aqueous media; wherein acid neutralizes base with the liberation of carbon dioxide and formation of acid salt and water. The effervescent compositions comprising chlorpromazine or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction. The carbon dioxide produced by effervescent reaction allows enhanced permeability of chlorpromazine or salt thereof due to an alteration of the paracellular and transcellular pathway. The carbon dioxide produced by effervescent reaction alters (widens) the intercellular space between cells, which leads to greater absorption of active ingredients and also it promotes transcellular absorption by Inducing a change in the cell membrane structure. The effervescent compositions comprising chlorpromazine or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction. The said dosage form allows minimum loss of chlorpromazine through first pass metabolism results in increased systemic bioavailability of chlorpromazine in the treatment of psychotic disorders.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention show quick disintegration and dissolution upon contact with water. The effervescent composition of the present invention when formulated as tablet has a disintegration time of about 300 seconds or less. Preferably, the disintegration time of the effervescent tablet is about 180 seconds or less and more preferably about 90 seconds or less. The disintegration time is measured in 200 ml of water at room temperature of about 25°C±5°C.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention upon dissolution has pH ranges from 3 to 6.5. The pH is measured in 200 ml of water at room temperature of about 25°C±5°C. The effervescent compositions comprising chlorpromazine or salt thereof of the present invention has pleasant taste which allows patient acceptability and better compliance in the treatment psychotic disorder.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention can be made up of any weight with suitable quantities of chlorpromazine or salt thereof and pharmaceutically acceptable excipient.
The other physical parameters of effervescent compositions of present invention like appearance, thickness, weight variation, hardness, friability, smell, taste, after taste were found to be satisfactory. In another aspect of the present invention is to provide method of treating psychotic disorders by administering effervescent composition comprising chlorpromazine or salt thereof. The concentrations of active ingredient and excipient in the effervescent compositions has been optimized which allows better patient compliance in the treatment of psychotic disorders, schizophrenia, nausea and vomiting, for relief of restlessness and apprehension before surgery, acute intermittent porphyria, adjunct in the treatment of tetanus, manic type of manic-depressive illness, relief of intractable hiccups with less adverse effect such as Drowsiness, Jaundice, Hematological Disorders, Agranulocytosis, Hypotensive Effects, electrocardiogram Changes, Extrapyramidal Symptoms, Class effect, Motor Restless ness, Pseudo parkinsonism, Tardive Dyskinesia, Behavioral Effects, Other CNS Effects such as Neuroleptic Malignant Syndrome, Cerebral edema, Convulsive seizures, Allergic Reactions such as mild urticarial type of photosensitivity, exfoliative dermatitis, Contact dermatitis, Endocrine Disorders, Autonomic Reactions, Skin Pigmentation and Ocular Changes.
The effervescent compositions comprising chlorpromazine or salt thereof of the present invention can be packaged in suitable air tight containers, moisture proof packs and optionally oxygen busters.
EXAMPLES:
The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
Example 1 :
Figure imgf000014_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Polyvinylprrolidone, and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with part quantity Magnesium stearate of step 2.
4. The blend of step 3 was fed into Roller compactor to obtain flex/ribbons.
5. Obtained flex/ribbons were milled using co-mill fitted with suitable screen.
6. Milled granules of step-5 were mixed with previously weighed and sifted Sucralose and Peppermint flavor (ASTM#40) and lubricated by mixing with remaining quantity of Magnesium stearate of step -2.
7. The blend of step 6 was compressed using suitable tooling fitted to compression machine. Example 2:
Figure imgf000015_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate and Mannitol were sifted through ASTM #40 and mixed in a granulator.
2. Prepared binder solution by dissolving Polyvinylpyrrolidone in Isopropyl alcohol.
3. Raw materials from Step-1 were granulated using binder of step -2; obtained granules were dried and milled.
4. Milled granules were mixed with sifted Citric acid, Sodium Citrate, Sodium bicarbonate, Sucralose, Sour cherry flavor and Colloidal silicon dioxide.
5. Magnesium stearate was sifted through ASTM #60.
6. The blend of step 4 was lubricated with Magnesium stearate of step 5.
7. The blend of step 6 was compressed into tablet using tablet compression machine. Example 3:
Figure imgf000016_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 4:
Figure imgf000016_0002
Figure imgf000017_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid, Tartaric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 5:
Figure imgf000017_0002
Figure imgf000018_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium carbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid was sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 6:
Figure imgf000018_0002
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium carbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 7:
Figure imgf000019_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid, Tartaric acid and Sodium citrate were sifted through #20 and mixed. 2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 8:
Figure imgf000020_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine. Example 9:
Figure imgf000021_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 10:
Figure imgf000021_0002
Figure imgf000022_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 11 :
Figure imgf000022_0002
Figure imgf000023_0001
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor, Orange flavor and Colloidal silicon dioxide were sifted through ASTM #40; Tartaric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.
Example 12:
Figure imgf000023_0002
Manufacturing Process:
1. Chlorpromazine hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinylpyrrolidone, Peppermint flavor and Colloidal silicon dioxide were sifted through ASTM #40; Citric acid and Sodium citrate were sifted through #20 and mixed.
2. Magnesium stearate was sifted through ASTM #60.
3. The blend of step 1 was lubricated with Magnesium stearate of step 2.
4. The blend of step 3 was compressed into tablet using tablet compression machine.

Claims

1. An effervescent composition comprising Chlorpromazine or salts thereof.
2. An effervescent composition comprising Chlorpromazine or salts thereof; at least one acidic agent and at least one basic agent.
3. An effervescent composition according to claim 2, wherein acidic agent is selected from the group consisting of citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof.
4. An effervescent composition according to claims 2 and 3, wherein acidic agent is preferably citric acid, tartaric acid or mixture thereof.
5. An effervescent composition according to claims 2, 3 and 4, wherein the amount of the acid agent ranges from about 3% to about 45% by weight of composition.
6. An effervescent composition according to claim 2, wherein basic agent is selected from the group consisting of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate, glycine carbonate or mixture thereof.
7. An effervescent composition according to claims 2 and 6, wherein basic agent is preferably sodium bicarbonate, sodium carbonate or mixture thereof.
8. An effervescent composition according to claims 2, 6 and 7, wherein the amount of the basic agent ranges from about 20% to 50% by total weight of composition.
9. An effervescent composition according to claim 2, wherein the ratio of acidic agent to basic agent ranges from 1 :3 to 3:1.
10. An effervescent composition according to claims 1 and 2, further comprises one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, antioxidant, lubricant, glidant and coloring agents.
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